In 1989 the Committee on Diet and Health of the National Research Council issued a comprehensive report entitled "Diet and Health," which concluded that the American diet is an important factor contributing to the development of several major chronic diseases, including cancer. With regard to breast cancer in particular, recent epidemiological studies have provided supportive evidence for a positive association between alcohol intake and breast cancer risk. Yet experimental evidence for an influence of alcohol consumption on mammary carcinogenesis is limited. Such additional evidence is clearly needed so that reliable, dietary alcohol recommendations can be offered to those women at highest risk. The objective of the proposed investigations is to clearly establish a dose-response relationship between chronic ethanol intake and the enhancement of chemically-induced mammary tumorigenesis (observed in our preliminary studies) and to determine mechanisms for the ethanol effect. Prior ethanol intakes that produce low to high blood ethanol levels will be examined for an ability to enhance mammary tumorigenesis induced by both direct- and indirect-acting mammary carcinogens. The remainder of the proposal will then focus on two major mechanisms whereby ethanol could enhance mammary tumorigenesis. First, an effect of ethanol intake in inhibiting the repair of carcinogen-induced mammary DNA damage and the activities of mammary DNA repair enzymes will be examined. The roles of ethanol and acetaldehyde in mediating any inhibition of DNA repair enzymes also will be studied. The basis whereby ethanol consumption can delay the maturation of the normal mammary epithelium, an alteration which enhances susceptibility to mammary tumorigenesis, then will be examined. The density and DNA-labeling index of carcinogen-sensitive terminal end buds will be studied. Hormonal control of mammary gland maturation as influenced by ethanol intake also will be evaluated by investigating serum prolactin, estradiol and progesterone as well as the mammary gland content of receptors for these hormones (as measured by radioimmunoassay). The results from the proposed experiments should characterize important mechanisms whereby ethanol intake can enhance breast tumorigenesis. Since breast cancer is a leading cause of cancer-related death among U.S. women and due to the widespread American consumption of alcohol, further research is certainly warranted in order to understand and minimize the risk associated with alcohol intake.